Ziagen

1.

NAME OF THE MEDICINAL PRODUCT

Ziagen 300 mg film-coated tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 300 mg of abacavir (as sulfate).

For a full list of excipients see section 6.1.

3.

PHARMACEUTICAL FORM

Film-coated tablet (tablets)

The scored tablets are yellow, biconvex, capsule shaped and are engraved with ‘GX 623’ on both

sides.

The tablet can be divided into equal halves.

4.

CLINICAL PARTICULARS

4.1 Therapeutic indications

Ziagen is indicated in antiretroviral combination therapy for the treatment of Human

Immunodeficiency Virus (HIV) infection.

The demonstration of the benefit of Ziagen is mainly based on results of studies performed with a

twice daily regimen, in treatment-naïve adult patients on combination therapy (see section 5.1).

Before initiating treatment with abacavir, screening for carriage of the HLA-B*5701 allele should be

performed in any HIV-infected patient, irrespective of racial origin. Screening is also recommended

prior to re-initiation of abacavir in patients of unknown HLA-B*5701 status who have previously

tolerated abacavir (see “Management after an interruption of Ziagen therapy”). Abacavir should not

be used in patients known to carry the HLA-B*5701 allele, unless no other therapeutic option is

available in these patients, based on the treatment history and resistance testing (see section 4.4 and

4.8).

4.2 Posology and method of administration

Ziagen should be prescribed by physicians experienced in the management of HIV infection.

Ziagen can be taken with or without food.

To ensure administration of the entire dose, the tablet(s) should ideally be swallowed without

crushing.

Ziagen is also available as an oral solution for use in children over three months of age and weighing

less than 14 kg and for those patients for whom the tablets are inappropriate.

Alternatively, for patients who are unable to swallow tablets, the tablet(s) may be crushed and added

to a small amount of semi-solid food or liquid, all of which should be consumed immediately (see

section 5.2).

2

Adults and adolescents (over 12 years of age): the recommended dose of Ziagen is 600 mg daily. This

may be administered as either 300 mg (one tablet) twice daily or 600 mg (two tablets) once daily (see

sections 4.4 and 5.1).

Patients changing to the once daily regimen should take 300 mg twice a day and switch to 600 mg

once a day the following morning. Where an evening once daily regimen is preferred, 300 mg of

Ziagen should be taken on the first morning only, followed by 600 mg in the evening. When changing

back to a twice daily regimen, patients should complete the day's treatment and start 300 mg twice a

day the following morning.

Children (under 12 years of age):

A dosing according to weight bands is recommended for Ziagen tablets. This dosing regimen for

paediatric patients weighing 14-30 kg is based primarily on pharmacokinetic modelling. A

pharmacokinetic overexposure of abacavir can occur since accurate dosing can not be achieved with

this formulation. Therefore a close safety monitoring is warranted in these patients.

Children weighing at least 30 kg: the adult dosage of 300 mg twice daily should be taken.

Children weighing > 21 kg to < 30 kg: one half of a Ziagen tablet taken in the morning and one whole

tablet taken in the evening.

Children weighing 14 to 21 kg: one half of a Ziagen tablet twice daily.

Children less than three months: the experience in children aged less than three months is limited (see

section 5.2).

Renal impairment : no dosage adjustment of Ziagen is necessary in patients with renal dysfunction.

However, Ziagen is not recommended for patients with end-stage renal disease (see section 5.2).

Hepatic impairment: abacavir is primarily metabolised by the liver. No dose recommendation can be

made in patients with mild hepatic impairment. In patients with moderate hepatic impairment, no data

are available, therefore the use of abacavir is not recommended unless judged necessary. If abacavir is

used in patients with mild or moderate hepatic impairment, then close monitoring is required, and if

feasible, monitoring of abacavir plasma levels is recommended (see section 5.2). Abacavir is

contraindicated in patients with severe hepatic impairment (see section 4.3 and 4.4).

Elderly: no pharmacokinetic data is currently available in patients over 65 years of age.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients. See BOXED INFORMATION ON

HYPERSENSITIVITY REACTIONS in sections 4.4. and 4.8.

Severe hepatic impairment.

4.4 Special warnings and precautions for use

Hypersensitivity reaction (see also section 4.8) :

In a clinical study, 3.4 % of subjects with a negative HLA-B*5701 status receiving abacavir

developed a hypersensitivity reaction.

Studies have shown that carriage of the HLA-B*5701 allele is associated with a significantly

increased risk of a hypersensitivity reaction to abacavir. Based on the prospective study CNA106030

(PREDICT-1), use of pre-therapy screening for the HLA-B*5701 allele and subsequently avoiding

abacavir in patients with this allele significantly reduced the incidence of abacavir hypersensitivity

3

reactions. In populations similar to that enrolled in the PREDICT-1 study , it is estimated that 48% to

61% of patients with the HLA-B*5701 allele will develop a hypersensitivity reaction during the

course of abacavir treatment compared with 0% to 4% of patients who do not have the HLA-B*5701

allele.

These results are consistent with those of prior retrospective studies.

As a consequence, before initiating treatment with abacavir, screening for carriage of the HLA-

B*5701 allele should be performed in any HIV-infected patient, irrespective of racial origin.

Screening is also recommended prior to re-initiation of abacavir in patients of unknown HLA-B*5701

status who have previously tolerated abacavir (see “Management after an interruption of Ziagen

therapy”). Abacavir should not be used in patients known to carry the HLA-B*5701 allele, unless no

other therapeutic option is available based on the treatment history and resistance testing (see section

4.1).

In any patient treated with abacavir, the clinical diagnosis of suspected hypersensitivity reaction must

remain the basis of clinical decision-making. It is noteworthy that among patients with a clinically

suspected hypersensitivity reaction, a proportion did not carry HLA-B*5701. Therefore, even in the

absence of HLA-B*5701 allele, it is important to permanently discontinue abacavir and not

rechallenge with abacavir if a hypersensitivity reaction cannot be ruled out on clinical grounds, due to

the potential for a severe or even fatal reaction.

Skin patch testing was used as a research tool for the PREDICT-1 study but has no utility in the

clinical management of patients and therefore should not be used in the clinical setting.

•

Clinical description

Hypersensitivity reactions are characterised by the appearance of symptoms indicating multi-organ

system involvement. Almost all hypersensitivity reactions will have fever and/or rash as part of the

syndrome.

Other signs and symptoms may include respiratory signs and symptoms such as dyspnoea, sore throat,

cough and abnormal chest x-ray findings (predominantly infiltrates, which can be localised),

gastrointestinal symptoms, such as nausea, vomiting, diarrhoea, or abdominal pain, and may lead to

misdiagnosis of hypersensitivity as respiratory disease (pneumonia, bronchitis, pharyngitis), or

gastroenteritis. Other frequently observed signs or symptoms of the hypersensitivity reaction may

include lethargy or malaise and musculoskeletal symptoms (myalgia, rarely myolysis, arthralgia).

The symptoms related to this hypersensitivity reaction worsen with continued therapy and can be life-

threatening. These symptoms usually resolve upon discontinuation of Ziagen.

•

Clinical management

Hypersensitivity reaction symptoms usually appear within the first six weeks of initiation of treatment

with abacavir, although these reactions may occur at any time during therapy. Patients should be

monitored closely, especially during the first two months of treatment with Ziagen, with consultation

every two weeks.

Regardless of their HLA-B*5701 status, patients who are diagnosed with a hypersensitivity reaction

whilst on therapy MUST discontinue Ziagen immediately.

Ziagen, or any other medicinal product containing abacavir (e.g. Kivexa, Trizivir), MUST

NEVER be restarted in patients who have stopped therapy due to a hypersensitivity reaction.

Restarting abacavir following a hypersensitivity reaction results in a prompt return of symptoms

within hours. This recurrence is usually more severe than on initial presentation, and may include life-

threatening hypotension and death.

4

To avoid a delay in diagnosis and minimise the risk of a life-threatening hypersensitivity reaction,

Ziagen must be permanently discontinued if hypersensitivity cannot be ruled out, even when other

diagnoses are possible (respiratory diseases, flu-like illness, gastroenteritis or reactions to other

medications).

Special care is needed for those patients simultaneously starting treatment with Ziagen and other

medicinal products known to induce skin toxicity (such as non-nucleoside reverse transcriptase

inhibitors - NNRTIs). This is because it is currently difficult to differentiate between rashes induced

by these products and abacavir related hypersensitivity reactions.

•

Management after an interruption of Ziagen therapy

Regardless of a patient’s HLA-B*5701 status, if therapy with Ziagen has been discontinued for any

reason and restarting therapy is under consideration, the reason for discontinuation must be

established to assess whether the patient had any symptoms of a hypersensitivity reaction. If a

hypersensitivity reaction cannot be ruled out, Ziagen or any other medicinal product containing

abacavir (e.g. Kivexa, Trizivir ) must not be restarted.

Hypersensitivity reactions with rapid onset, including life-threatening reactions have occurred

after restarting Ziagen in patients who had only one of the key symptoms of hypersensitivity

(skin rash, fever, gastrointestinal, respiratory or constitutional symptoms such as lethargy and

malaise) prior to stopping Ziagen. The most common isolated symptom of a hypersensitivity

reaction was a skin rash. Moreover , on very rare occasions hypersensitivity reactions have been

reported in patients who have restarted therapy, and who had no preceding symptoms of a

hypersensitivity reaction (i.e. patients previously considered to be abacavir tolerant). In both

cases , if a decision is made to restart Ziagen this must be done in a setting where medical assistance is

readily available.

Screening for carriage of the HLA B*5701 allele is recommended prior to re-initiation of abacavir in

patients of unknown HLA-B*5701 status who have previously tolerated abacavir. Re-initiation of

abacavir in such patients who test positive for the HLA B*5701 allele is not recommended and should

be considered only under exceptional circumstances where potential benefit outweighs the risk and

with close medical supervision.

•

Essential patient information

Prescribers must ensure that patients are fully informed regarding the following information on the

hypersensitivity reaction:

- patients must be made aware of the possibility of a hypersensitivity reaction to abacavir that

may result in a life-threatening reaction or death and that the risk of a hypersensitivity

reaction is increased if they are HLA-B*5701 positive.

- patients must also be informed that a HLA-B*5701 negative patient can also experience an

abacavir hypersensitivity reaction. Therefore, ANY patient who develops signs or symptoms

consistent with a possible hypersensitivity reaction to abacavir MUST CONTACT THEIR

DOCTOR IMMEDIATELY.

- patients who are hypersensitive to abacavir should be reminded that they must never take

Ziagen or any other medicinal product containing abacavir (e.g. Kivexa, Trizivir) again,

regardless of their HLA-B*5701 status.

- in order to avoid restarting Ziagen, patients who have experienced a hypersensitivity reaction

- patients who have stopped Ziagen for any reason, and particularly due to possible adverse

reactions or illness, must be advised to contact their doctor before restarting.

5

should be asked to return the remaining Ziagen tablets or oral solution to the pharmacy.

- each patient should be reminded to read the Package Leaflet included in the Ziagen pack.

They should be reminded of the importance of removing the Alert Card included in the pack,

and keeping it with them at all times.

Lactic acidosis: lactic acidosis, usually associated with hepatomegaly and hepatic steatosis, has been

reported with the use of nucleoside analogues. Early symptoms (symptomatic hyperlactatemia)

include benign digestive symptoms (nausea, vomiting and abdominal pain), non-specific malaise, loss

of appetite, weight loss, respiratory symptoms (rapid and/or deep breathing) or neurological symptoms

(including motor weakness).

Lactic acidosis has a high mortality and may be associated with pancreatitis, liver failure, or renal

failure.

Lactic acidosis generally occurred after a few or several months of treatment.

Treatment with nucleoside analogues should be discontinued in the setting of symptomatic

hyperlactatemia and metabolic/lactic acidosis, progressive hepatomegaly, or rapidly elevating

aminotransferase levels.

Caution should be exercised when administering nucleoside analogues to any patient (particularly

obese women) with hepatomegaly, hepatitis or other known risk factors for liver disease and hepatic

steatosis (including certain medicinal products and alcohol). Patients co-infected with hepatitis C and

treated with alpha interferon and ribavirin may constitute a special risk.

Patients at increased risk should be followed closely.

Mitochondrial dysfunction: nucleoside and nucleotide analogues have been demonstrated in vitro and

in vivo to cause a variable degree of mitochondrial damage. There have been reports of mitochondrial

dysfunction in HIV-negative infants exposed in utero and/or post-natally to nucleoside analogues. The

main adverse reactions reported are haematological disorders (anaemia, neutropenia), metabolic

disorders (hyperlactatemia, hyperlipasemia). These events are often transitory. Some late-onset

neurological disorders have been reported (hypertonia, convulsion, abnormal behaviour). Whether the

neurological disorders are transient or permanent is currently unknown. Any child exposed in utero to

nucleoside and nucleotide analogues, even HIV-negative children, should have clinical and laboratory

follow-up and should be fully investigated for possible mitochondrial dysfunction in case of relevant

signs or symptoms. These findings do not affect current national recommendations to use antiretroviral

therapy in pregnant women to prevent vertical transmission of HIV.

Lipodystrophy: combination antiretroviral therapy has been associated with the redistribution of body

fat (lipodystrophy) in HIV patients. The long-term consequences of these events are currently

unknown. Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis

and protease inhibitors (PIs) and lipoatrophy and nucleoside reverse transcriptase inhibitors (NRTIs)

has been hypothesised. A higher risk of lipodystrophy has been associated with individual factors such

as older age, and with drug related factors such as longer duration of antiretroviral treatment and

associated metabolic disturbances. Clinical examination should include evaluation for physical signs

of fat redistribution. Consideration should be given to the measurement of fasting serum lipids and

blood glucose. Lipid disorders should be managed as clinically appropriate (see section 4.8).

Pancreatitis : pancreatitis has been reported, but a causal relationship to abacavir treatment is

uncertain.

Triple nucleoside therapy: in patients with high viral load (>100,000 copies/ml) the choice of a triple

combination with abacavir, lamivudine and zidovudine needs special consideration (see section 5.1).

6

There have been reports of a high rate of virological failure and of emergence of resistance at an early

stage when abacavir was combined with tenofovir disoproxil fumarate and lamivudine as a once daily

regimen.

Liver disease : the safety and efficacy of Ziagen has not been established in patients with significant

underlying liver disorders. Ziagen is contraindicated in patients with severe hepatic impairment (see

section 4.3). Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy

are at an increased risk of severe and potentially fatal hepatic adverse reactions. In case of concomitant

antiviral therapy for hepatitis B or C, please refer also to the relevant product information for these

medicinal products.

Patients with pre-existing liver dysfunction, including chronic active hepatitis, have an increased

frequency of liver function abnormalities during combination antiretroviral therapy, and should be

monitored according to standard practice. If there is evidence of worsening liver disease in such

patients, interruption or discontinuation of treatment must be considered.

A pharmacokinetic study has been performed in patients with mild hepatic impairment. However, a

definitive recommendation on dose reduction is not possible due to substantial variability of drug

exposure in this patient population (see section 5.2). The clinical safety data available with abacavir in

hepatically impaired patients is very limited. Due to the potential increases in exposure (AUC) in some

patients, close monitoring is required. No data are available in patients with moderate or severe

hepatic impairment. Plasma concentrations of abacavir are expected to substantially increase in these

patients. Therefore, the use of abacavir in patients with moderate hepatic impairment is not

recommended unless judged necessary and requires close monitoring of these patients.

Renal disease: Ziagen should not be administered to patients with end-stage renal disease (see section

5.2).

Immune Reactivation Syndrome : In HIV-infected patients with severe immune deficiency at the time

of institution of combination antiretroviral therapy (CART), an inflammatory reaction to

asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or

aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or

months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or

focal mycobacterium infections, and Pneumocystis carinii pneumonia. Any inflammatory symptoms

should be evaluated and treatment instituted when necessary.

Osteonecrosis: Although the aetiology is considered to be multifactorial (including corticosteroid use,

alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis

have been reported particularly in patients with advanced HIV-disease and/or long-term exposure to

combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they

experience joint aches and pain, joint stiffness or difficulty in movement.

Opportunistic infections: patients receiving Ziagen or any other antiretroviral therapy may still

develop opportunistic infections and other complications of HIV infection. Therefore patients should

remain under close clinical observation by physicians experienced in the treatment of these associated

HIV diseases.

Transmission: patients should be advised that current antiretroviral therapy, including Ziagen, have

not been proven to prevent the risk of transmission of HIV to others through sexual contact or blood

contamination. Appropriate precautions should continue to be taken.

Myocardial Infarction: Observational studies have shown an association between myocardial

infarction and the use of abacavir. Those studied were mainly antiretroviral experienced patients. Data

from clinical trials showed limited numbers of myocardial infarction and could not exclude a small

increase in risk. Overall the available data from observational cohorts and from randomised trials

show some inconsistency so can neither confirm nor refute a causal relationship between abacavir

treatment and the risk of myocardial infarction. To date, there is no established biological mechanism

7

to explain a potential increase in risk. When prescribing Ziagen, action should be taken to try to

minimize all modifiable risk factors (e.g. smoking, hypertension, and hyperlipidaemia).

4.5 Interaction with other medicinal products and other forms of interaction

Based on the results of in vitro experiments and the known major metabolic pathways of abacavir, the

potential for P450 mediated interactions with other medicinal products involving abacavir is low.

P450 does not play a major role in the metabolism of abacavir, and abacavir does not inhibit

metabolism mediated by CYP 3A4. Abacavir has also been shown in vitro not to inhibit CYP 3A4,

CYP2C9 or CYP2D6 enzymes at clinically relevant concentrations. Induction of hepatic metabolism

has not been observed in clinical studies. Therefore, there is little potential for interactions with

antiretroviral PIs and other medicinal products metabolised by major P450 enzymes. Clinical studies

have shown that there are no clinically significant interactions between abacavir, zidovudine, and

lamivudine.

Potent enzymatic inducers such as rifampicin, phenobarbital and phenytoin may via their action on

UDP-glucuronyltransferases slightly decrease the plasma concentrations of abacavir.

Ethanol: the metabolism of abacavir is altered by concomitant ethanol resulting in an increase in AUC

of abacavir of about 41%. These findings are not considered clinically significant. Abacavir has no

effect on the metabolism of ethanol.

Methadone : in a pharmacokinetic study, co-administration of 600 mg abacavir twice daily with

methadone showed a 35% reduction in abacavir C max and a one hour delay in t max but the AUC was

unchanged. The changes in abacavir pharmacokinetics are not considered clinically relevant. In this

study abacavir increased the mean methadone systemic clearance by 22%. The induction of drug

metabolising enzymes cannot therefore be excluded. Patients being treated with methadone and

abacavir should be monitored for evidence of withdrawal symptoms indicating under dosing, as

occasionally methadone re-titration may be required.

Retinoids: retinoid compounds are eliminated via alcohol dehydrogenase. Interaction with abacavir is

possible but has not been studied.

4.6 Pregnancy and lactation

Ziagen is not recommended during pregnancy. The safe use of abacavir in human pregnancy has not

been established. Placental transfer of abacavir and/or its related metabolites has been shown to occur

in animals. Toxicity to the developing embryo and foetus occurred in rats, but not in rabbits (see

section 5.3). The teratogenic potential of abacavir could not be established from studies in animals.

Abacavir and its metabolites are secreted into the milk of lactating rats. It is expected that these will

also be secreted into human milk, although this has not been confirmed. There are no data available on

the safety of abacavir when administered to babies less than three months old. It is therefore

recommended that mothers do not breast-feed their babies while receiving treatment with abacavir.

Additionally, it is recommended that HIV infected women do not breast-feed their infants under any

circumstances in order to avoid transmission of HIV.

4.7 Effects on ability to drive and use machines

No studies on the effects on ability to drive and use machines have been performed.

4.8 Undesirable effects

Hypersensitivity (see also section 4.4):

In a clinical study, 3.4 % of subjects with a negative HLA-B*5701 status receiving abacavir

8

developed a hypersensitivity reaction. In clinical studies with abacavir 600 mg once daily the

reported rate of hypersensitivity remained within the range recorded for abacavir 300 mg twice

daily.

Some hypersensitivity reactions were life-threatening and resulted in fatal outcome despite taking

precautions. This reaction is characterised by the appearance of symptoms indicating multi-

organ/body-system involvement.

Almost all patients developing hypersensitivity reactions will have fever and/or rash (usually

maculopapular or urticarial) as part of the syndrome, however reactions have occurred without

rash or fever.

The signs and symptoms of this hypersensitivity reaction are listed below. These have been

identified either from clinical studies or post marketing surveillance. Those reported in at least

10% of patients with a hypersensitivity reaction are in bold text.

Skin

Rash (usually maculopapular or urticarial)

Gastrointestinal tract

Nausea, vomiting, diarrhoea, abdominal pain , mouth ulceration

Respiratory tract

Dyspnoea, cough , sore throat, adult respiratory distress

syndrome, respiratory failure

Miscellaneous

Fever, lethargy, malaise , oedema, lymphadenopathy,

hypotension, conjunctivitis, anaphylaxis

Neurological/Psychiatry

Headache , paraesthesia

Haematological

Lymphopenia

Liver/pancreas

Elevated liver function tests, hepatitis, hepatic failure

Musculoskeletal

Myalgia , rarely myolysis, arthralgia, elevated creatine

phosphokinase

Urology

Elevated creatinine, renal failure

Rash (81% vs 67% respectively) and gastrointestinal manifestations (70% vs 54%

respectively) were more frequently reported in children compared to adults.

Some patients with hypersensitivity reactions were initially thought to have gastroenteritis,

respiratory disease (pneumonia, bronchitis, pharyngitis) or a flu-like illness. This delay in

diagnosis of hypersensitivity has resulted in Ziagen being continued or re-introduced, leading to

more severe hypersensitivity reactions or death. Therefore, the diagnosis of hypersensitivity

reaction should be carefully considered for patients presenting with symptoms of these diseases.

Symptoms usually appeared within the first six weeks (median time to onset 11 days) of initiation

of treatment with abacavir, although these reactions may occur at any time during therapy. Close

medical supervision is necessary during the first two months, with consultations every two weeks.

It is likely that intermittent therapy may increase the risk of developing sensitisation and therefore

occurrence of clinically significant hypersensitivity reactions. Consequently, patients should be

advised of the importance of taking Ziagen regularly.

Restarting Ziagen following a hypersensitivity reaction results in a prompt return of symptoms

within hours. This recurrence of the hypersensitivity reaction is usually more severe than on initial

presentation, and may include life-threatening hypotension and death. Regardless of their HLA-

9

B*5701 status, patients who develop this hypersensitivity reaction must discontinue Ziagen

and must never be rechallenged with Ziagen, or any other medicinal product containing

abacavir (e.g. Kivexa, Trizivir).

To avoid a delay in diagnosis and minimise the risk of a life-threatening hypersensitivity reaction,

Ziagen must be permanently discontinued if hypersensitivity cannot be ruled out, even when other

diagnoses are possible (respiratory diseases, flu-like illness, gastroenteritis or reactions to other

medications).

Hypersensitivity reactions with rapid onset, including life-threatening reactions have

occurred after restarting Ziagen in patients who had only one of the key symptoms of

hypersensitivity (skin rash, fever, gastrointestinal, respiratory or constitutional symptoms

such as lethargy and malaise) prior to stopping Ziagen. The most common isolated symptom

of a hypersensitivity reaction was a skin rash. Moreover, on very rare occasions

hypersensitivity reactions have been reported in patients who have restarted therapy and

who had no preceding symptoms of a hypersensitivity reaction. In both cases, if a decision is

made to restart Ziagen this must be done in a setting where medical assistance is readily available.

Each patient must be warned about this hypersensitivity reaction to abacavir.

For many of the other adverse reactions reported, it is unclear whether they are related to Ziagen, to

the wide range of medicinal products used in the management of HIV infection or as a result of the

disease process.

Many of those listed below occur commonly (nausea, vomiting, diarrhoea, fever, lethargy, rash) in

patients with abacavir hypersensitivity. Therefore, patients with any of these symptoms should be

carefully evaluated for the presence of this hypersensitivity reaction. If Ziagen has been discontinued

in patients due to experiencing any one of these symptoms and a decision is made to restart a

medicinal product containing abacavir, this must be done in a setting where medical assistance is

readily available (see section 4.4.). Very rarely cases of erythema multiforme, Stevens Johnson

syndrome or toxic epidermal necrolysis have been reported where abacavir hypersensitivity could not

be ruled out. In such cases medicinal products containing abacavir should be permanently

discontinued.

Many of the adverse reactions have not been treatment limiting. The following convention has been

used for their classification: very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1,000

to <1/100), rare (>1/10,000 to <1/1,000) very rare (<1/10,000).

Metabolism and nutrition disorders

Common: anorexia

Nervous system disorders

Common : headache

Gastrointestinal disorders

Common : nausea, vomiting, diarrhoea

Rare: pancreatitis

Skin and subcutaneous tissue disorders

Common : rash (without systemic symptoms)

Very rare : erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis

General disorders and administration site conditions

Common : fever, lethargy, fatigue

Cases of lactic acidosis, sometimes fatal, usually associated with severe hepatomegaly and hepatic

steatosis, have been reported with the use of nucleoside analogues (see section 4.4).

10

Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy)

in HIV patients including the loss of peripheral and facial subcutaneous fat, increased intra-abdominal

and visceral fat, breast hypertrophy and dorsocervical fat accumulation (buffalo hump).

Combination antiretroviral therapy has been associated with metabolic abnormalities such as

hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and

hyperlactataemia (see section 4.4).

In HIV-infected patients with severe immune deficiency at the time of initiation of combination

antiretroviral therapy (CART) an inflammatory reaction to asymptomatic or residual opportunistic

infections may arise (see section 4.4).

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk

factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART).

The frequency of this is unknown (see section 4.4).

Laboratory abnormalities

In controlled clinical studies laboratory abnormalities related to Ziagen treatment were uncommon,

with no differences in incidence observed between Ziagen treated patients and the control arms.

4.9 Overdose

Single doses up to 1200 mg and daily doses up to 1800 mg of Ziagen have been administered to

patients in clinical studies. No additional adverse reactions to those reported for normal doses were

reported. The effects of higher doses are not known. If overdose occurs the patient should be

monitored for evidence of toxicity (see section 4.8), and standard supportive treatment applied as

necessary. It is not known whether abacavir can be removed by peritoneal dialysis or haemodialysis.

5.

PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: nucleoside reverse transcriptase inhibitors, ATC Code: J05AF06

Mechanism of action : Abacavir is a NRTI. It is a potent selective inhibitor of HIV-1 and HIV-2.

Abacavir is metabolised intracellularly to the active moiety, carbovir 5’- triphosphate (TP). In vitro

studies have demonstrated that its mechanism of action in relation to HIV is inhibition of the HIV

reverse transcriptase enzyme, an event which results in chain termination and interruption of the viral

replication cycle. Abacavir shows synergy in vitro in combination with nevirapine and zidovudine. It

has been shown to be additive in combination with didanosine, lamivudine and stavudine.

In vitro resistance : Abacavir-resistant isolates of HIV-1 have been selected in vitro and are associated

with specific genotypic changes in the reverse transcriptase (RT) codon region (codons M184V,

K65R, L74V and Y115F). Viral resistance to abacavir develops relatively slowly in vitro, requiring

multiple mutations for a clinically relevant increase in EC 50 over wild-type virus.

In vivo resistance (Therapy naïve patients) Isolates from most patients experiencing virological

failure with a regimen containing abacavir in pivotal clinical trials showed either no NRTI-related

changes from baseline (45%) or only M184V or M184I selection (45%). The overall selection

frequency for M184V or M184I was high (54%), and less common was the selection of L74V (5%),

K65R (1%) and Y115F (1%). The inclusion of zidovudine in the regimen has been found to reduce

the frequency of L74V and K65R selection in the presence of abacavir (with zidovudine: 0/40, without

zidovudine: 15/192, 8%).

11

Therapy

Abacavir +

Combivir 1

Abacavir +

lamivudine +

NNRTI

Abacavir +

lamivudine +

PI (or

PI/ritonavir)

Total

Number of

Subjects

282

1094

909

2285

Number of

Virological

Failures

43

90

158

306

Number of

On-Therapy

Genotypes

40 (100%)

51 (100%) 2

141 (100%)

232 (100%)

K65R

0

1 (2%)

2 (1%)

3 (1%)

L74V

0

9 (18%)

3 (2%)

12 (5%)

Y115F

0

2 (4%)

0

2 (1%)

M184V/I

34 (85%)

22 (43%)

70 (50%)

126 (54%)

TAMs 3

3 (8%)

2 (4%)

4 (3%)

9 (4%)

1.Combivir is a fixed dose combination of lamivudine and zidovudine

2.Includes three non-virological failures and four unconfirmed virological failures.

3. Number of subjects with ≥ 1 Thymidine Analogue Mutations (TAMs).

TAMs might be selected when thymidine analogs are associated with abacavir. In a meta-analysis of

six clinical trials, TAMs were not selected by regimens containing abacavir without zidovudine

(0/127), but were selected by regimens containing abacavir and the thymidine analogue zidovudine

(22/86, 26%).

In vivo resistance (Therapy experienced patients): Clinically significant reduction of susceptibility to

abacavir has been demonstrated in clinical isolates of patients with uncontrolled viral replication, who

have been pre-treated with and are resistant to other nucleoside inhibitors. In a meta-analysis of five

clinical trials where abacavir was added to intensify therapy, of 166 subjects, 123 (74%) had M184V/I,

50 (30%) had T215Y/F, 45 (27%) had M41L, 30 (18%) had K70R and 25 (15%) had D67N. K65R

was absent and L74V and Y115F were uncommon (≤3%). Logistic regression modelling of the

predictive value for genotype (adjusted for baseline plasma HIV-1 RNA [vRNA], CD4+ cell count,

number and duration of prior antiretroviral therapies), showed that the presence of 3 or more NRTI

resistance-associated mutations was associated with reduced response at Week 4 (p=0.015) or 4 or

more mutations at median Week 24 (p≤0.012). In addition, the 69 insertion complex or the Q151M

mutation, usually found in combination with A62V, V75I, F77L and F116Y, cause a high level of

resistance to abacavir.

12

Baseline

Reverse

Transcriptase

Mutation

Week 4

(n = 166)

n

Median

Change vRNA

(log 10 c/mL)

Percent with

<400 copies/mL

vRNA

None

15

-0.96

40%

M184V alone 75

-0.74

64%

Any one NRTI

mutation

82

-0.72

65%

Any two NRTI-

associated

mutations

22

-0.82

32%

Any three

NRTI-

associated

mutations

19

-0.30

5%

Four or more

NRTI-

associated

mutations

28

-0.07

11%

Phenotypic resistance and cross-resistance: Phenotypic resistance to abacavir requires M184V with at

least one other abacavir-selected mutation, or M184V with multiple TAMs. Phenotypic cross-

resistance to other NRTIs with M184V or M184I mutation alone is limited. Zidovudine, didanosine,

stavudine and tenofovir maintain their antiretroviral activities against such HIV-1 variants. The

presence of M184V with K65R does give rise to cross-resistance between abacavir, tenofovir,

didanosine and lamivudine, and M184V with L74V gives rise to cross-resistance between abacavir,

didanosine and lamivudine. The presence of M184V with Y115F gives rise to cross-resistance

between abacavir and lamivudine. Appropriate use of abacavir can be guided using currently

recommended resistance algorithms.

Cross-resistance between abacavir and antiretrovirals from other classes (e.g. PIs or NNRTIs) is

unlikely.

Clinical Experience

The demonstration of the benefit of Ziagen is mainly based on results of studies performed in adult

treatment-naïve patients using a regimen of Ziagen 300 mg twice daily in combination with

zidovudine and lamivudine.

Twice daily (300 mg) administration:

•

Therapy naïve adults

In adults treated with abacavir in combination with lamivudine and zidovudine the proportion of

patients with undetectable viral load (<400 copies/ml) was approximately 70% (intention to treat

analysis at 48 weeks) with corresponding rise in CD4 cells.

One randomised, double blind, placebo controlled clinical study in adults has compared the

combination of abacavir, lamivudine and zidovudine to the combination of indinavir, lamivudine and

zidovudine. Due to the high proportion of premature discontinuation (42% of patients discontinued

randomised treatment by week 48), no definitive conclusion can be drawn regarding the equivalence

between the treatment regimens at week 48. Although a similar antiviral effect was observed between

the abacavir and indinavir containing regimens in terms of proportion of patients with undetectable

viral load (≤400 copies/ml; intention to treat analysis (ITT), 47% versus 49%; as treated analysis (AT),

86% versus 94% for abacavir and indinavir combinations respectively), results favoured the indinavir

13

combination, particularly in the subset of patients with high viral load (>100,000 copies/ml at baseline;

ITT, 46% versus 55%; AT, 84% versus 93% for abacavir and indinavir respectively).

In a multicentre, double-blind, controlled study (CNA30024), 654 HIV-infected, antiretroviral

therapy-naïve patients were randomised to receive either abacavir 300 mg twice daily or zidovudine

300 mg twice daily, both in combination with lamivudine 150 mg twice daily and efavirenz 600 mg

once daily. The duration of double-blind treatment was at least 48 weeks. In the intent-to-treat (ITT)

population, 70% of patients in the abacavir group, compared to 69% of patients in the zidovudine

group, achieved a virologic response of plasma HIV-1 RNA ≤50 copies/ml by Week 48 (point

estimate for treatment difference: 0.8, 95% CI -6.3, 7.9). In the as treated (AT) analysis the difference

between both treatment arms was more noticeable (88% of patients in the abacavir group, compared to

95% of patients in the zidovudine group (point estimate for treatment difference: -6.8, 95% CI -11.8; -

1.7). However, both analyses were compatible with a conclusion of non-inferiority between both

treatment arms.

ACTG5095 was a randomised (1:1:1), double-blind, placebo-controlled trial performed in 1147

antiretroviral naïve HIV-1 infected adults, comparing 3 regimens: zidovudine (ZDV), lamivudine

(3TC), abacavir (ABC), efavirenz (EFV) vs ZDV/3TC/EFV vs ZDV/3TC/ABC. After a median

follow-up of 32 weeks, the tritherapy with the three nucleosides ZDV/3TC/ABC was shown to be

virologically inferior to the two other arms regardless of baseline viral load (< or > 100 000 copies/ml)

with 26% of subjects on the ZDV/3TC/ABC arm, 16% on the ZDV/3TC/EFV arm and 13% on the 4

drug arm categorised as having virological failure (HIV RNA >200 copies/ml). At week 48 the

proportion of subjects with HIV RNA <50 copies/ml were 63%, 80% and 86% for the

ZDV/3TC/ABC, ZDV/3TC/EFV and ZDV/3TC/ABC/EFV arms, respectively. The study Data Safety

Monitoring Board stopped the ZDV/3TC/ABC arm at this time based on the higher proportion of

patients with virologic failure. The remaining arms were continued in a blinded fashion. After a

median follow-up of 144 weeks, 25% of subjects on the ZDV/3TC/ABC/EFV arm and 26% on the

ZDV/3TC/EFV arm were categorised as having virological failure. There was no significant

difference in the time to first virologic failure (p=0.73, log-rank test) between the 2 arms. In this study,

addition of ABC to ZDV/3TC/EFV did not significantly improve efficacy.

ZDV/3TC/ABC ZDV/3TC/EFV

ZDV/3TC/ABC/EFV

Virologic failure (HIV

RNA >200 copies/ml)

32 weeks

26%

16%

13%

144 weeks

-

26%

25%

Virologic success (48

weeks HIV RNA < 50

copies/ml)

63%

80%

86%

•

Therapy naïve children

In a study comparing the unblinded NRTI combinations (with or without blinded nelfinavir) in

children, a greater proportion treated with abacavir and lamivudine (71%) or abacavir and zidovudine

(60%) had HIV-1 RNA ≤400 copies/ml at 48 weeks, compared with those treated with lamivudine and

zidovudine (47%)[ p=0.09, intention to treat analysis]. Similarly, greater proportions of children

treated with the abacavir containing combinations had HIV-1 RNA ≤50 copies/ml at 48 weeks (53%,

42% and 28% respectively, p=0.07).

•

Therapy experienced patients

In adults moderately exposed to antiretroviral therapy the addition of abacavir to combination

antiretroviral therapy provided modest benefits in reducing viral load (median change

0.44 log 10 copies/ml at 16 weeks).

In heavily NRTI pretreated patients the efficacy of abacavir is very low. The degree of benefit as part

of a new combination regimen will depend on the nature and duration of prior therapy which may

have selected for HIV-1 variants with cross-resistance to abacavir.

14

Once daily (600 mg) administration:

•

Therapy naïve adults

The once daily regimen of abacavir is supported by a 48 weeks multi-centre, double-blind, controlled

study (CNA30021) of 770 HIV-infected, therapy-naïve adults. These were primarily asymptomatic

HIV infected patients (CDC stage A). They were randomised to receive either abacavir 600 mg once

daily or 300 mg twice daily, in combination with efavirenz and lamivudine given once daily. Similar

clinical success (point estimate for treatment difference -1.7, 95% CI -8.4, 4.9) was observed for both

regimens. From these results, it can be concluded with 95% confidence that the true difference is no

greater than 8.4% in favour of the twice daily regimen. This potential difference is sufficiently small to

draw an overall conclusion of non-inferiority of abacavir once daily over abacavir twice daily.

There was a low, similar overall incidence of virologic failure (viral load >50 copies/ml) in both the

once and twice daily treatment groups (10% and 8% respectively). In the small sample size for

genotypic analysis, there was a trend toward a higher rate of NRTI-associated mutations in the once

daily versus the twice daily abacavir regimens. No firm conclusion could be drawn due to the limited

data derived from this study. Long term data with abacavir used as a once daily regimen (beyond 48

weeks) are currently limited.

•

Therapy experienced patients

In study CAL30001, 182 treatment-experienced patients with virologic failure were randomised and

received treatment with either the fixed-dose combination of abacavir/lamivudine (FDC) once daily or

abacavir 300 mg twice daily plus lamivudine 300 mg once daily, both in combination with tenofovir

and a PI or an NNRTI for 48 weeks. Results indicate that the FDC group was non-inferior to the

abacavir twice daily group, based on similar reductions in HIV-1 RNA as measured by average area

under the curve minus baseline (AAUCMB, -1.65 log 10 copies/ml versus -1.83 log 10 copies/ml

respectively, 95% CI -0.13, 0.38). Proportions with HIV-1 RNA < 50 copies/ml (50% versus 47%)

and < 400 copies/ml (54% versus 57%) were also similar in each group (ITT population). However, as

there were only moderately experienced patients included in this study with an imbalance in baseline

viral load between the arms, these results should be interpreted with caution.

In study ESS30008, 260 patients with virologic suppression on a first line therapy regimen containing

abacavir 300 mg plus lamivudine 150 mg, both given twice daily and a PI or NNRTI, were

randomised to continue this regimen or switch to abacavir/lamivudine FDC plus a PI or NNRTI for 48

weeks. Results indicate that the FDC group was associated with a similar virologic outcome (non-

inferior) compared to the abacavir plus lamivudine group, based on proportions of subjects with HIV-

1 RNA < 50 copies/ml (90% and 85% respectively, 95% CI -2.7, 13.5).

Additional information:

The safety and efficacy of Ziagen in a number of different multidrug combination regimens is still not

completely assessed (particularly in combination with NNRTIs).

Abacavir penetrates the cerebrospinal fluid (CSF) (see section 5.2), and has been shown to reduce

HIV-1 RNA levels in the CSF. However, no effects on neuropsychological performance were seen

when it was administered to patients with AIDS dementia complex.

5.2 Pharmacokinetic properties

Absorption: abacavir is rapidly and well absorbed following oral administration. The absolute

bioavailability of oral abacavir in adults is about 83%. Following oral administration, the mean time

(t max ) to maximal serum concentrations of abacavir is about 1.5 hours for the tablet formulation and

about 1.0 hour for the solution formulation.

15

At therapeutic dosages a dosage of 300 mg twice daily, the mean (CV) steady state C max and C min of

abacavir are approximately 3.00 μg/ml (30%) and 0.01 µg/ml (99%), respectively. The mean (CV)

AUC over a dosing interval of 12 hours was 6.02 μg.h/ml (29%), equivalent to a daily AUC of

approximately 12.0 μg.h/ml. The C max value for the oral solution is slightly higher than the tablet.

After a 600 mg abacavir tablet dose, the mean (CV) abacavir C max was approximately 4.26 μg/ml

(28%) and the mean (CV) AUC ∞ was 11.95 μg.h/ml (21%).

Food delayed absorption and decreased C max but did not affect overall plasma concentrations (AUC).

Therefore Ziagen can be taken with or without food.

Administration of crushed tablets with a small amount of semi-solid food or liquid would not be

expected to have an impact on the pharmaceutical quality, and would therefore not be expected to alter

the clinical effect. This conclusion is based on the physiochemical and pharmacokinetic data,

assuming that the patient crushes and transfers 100% of the tablet and ingests immediately.

Distribution: following intravenous administration, the apparent volume of distribution was about

0.8 l/kg, indicating that abacavir penetrates freely into body tissues.

Studies in HIV infected patients have shown good penetration of abacavir into the cerebrospinal fluid

(CSF), with a CSF to plasma AUC ratio of between 30 to 44%. The observed values of the peak

concentrations are 9 fold greater than the IC 50 of abacavir of 0.08 µg/ml or 0.26 µM when abacavir is

given at 600 mg twice daily .

Plasma protein binding studies in vitro indicate that abacavir binds only low to moderately (~49%) to

human plasma proteins at therapeutic concentrations. This indicates a low likelihood for interactions

with other medicinal products through plasma protein binding displacement.

Metabolism: abacavir is primarily metabolised by the liver with approximately 2% of the administered

dose being renally excreted, as unchanged compound. The primary pathways of metabolism in man

are by alcohol dehydrogenase and by glucuronidation to produce the 5’-carboxylic acid and 5’-

glucuronide which account for about 66% of the administered dose. The metabolites are excreted in

the urine.

Elimination: the mean half-life of abacavir is about 1.5 hours. Following multiple oral doses of

abacavir 300 mg twice a day there is no significant accumulation of abacavir. Elimination of abacavir

is via hepatic metabolism with subsequent excretion of metabolites primarily in the urine. The

metabolites and unchanged abacavir account for about 83% of the administered abacavir dose in the

urine. The remainder is eliminated in the faeces.

Intracellular pharmacokinetics

In a study of 20 HIV-infected patients receiving abacavir 300 mg twice daily, with only one 300 mg

dose taken prior to the 24 hour sampling period, the geometric mean terminal carbovir-TP intracellular

half-life at steady-state was 20.6 hours, compared to the geometric mean abacavir plasma half-life in

this study of 2.6 hours. In a crossover study in 27 HIV-infected patients, intracellular carbovir-TP

exposures were higher for the abacavir 600 mg once daily regimen (AUC 24,ss + 32 %, C max24,ss + 99 %

and C trough + 18 %) compared to the 300 mg twice daily regimen. Overall, these data support the use

of abacavir 600 mg once daily for the treatment of HIV infected patients. Additionally, the efficacy

and safety of abacavir given once daily has been demonstrated in a pivotal clinical study (CNA30021-

See section 5.1 Clinical experience).

Special populations

Hepatically impaired: abacavir is metabolised primarily by the liver. The pharmacokinetics of

abacavir have been studied in patients with mild hepatic impairment (Child-Pugh score 5-6) receiving

a single 600 mg dose. The results showed that there was a mean increase of 1.89 fold [1.32; 2.70] in

the abacavir AUC, and 1.58 [1.22; 2.04] fold in the elimination half-life. No recommendation on

16

dosage reduction is possible in patients with mild hepatic impairment due to the substantial variability

of abacavir exposure.

Renally impaired: abacavir is primarily metabolised by the liver with approximately 2% of abacavir

excreted unchanged in the urine. The pharmacokinetics of abacavir in patients with end-stage renal

disease is similar to patients with normal renal function. Therefore no dosage reduction is required in

patients with renal impairment. Based on limited experience Ziagen should be avoided in patients with

end-stage renal disease.

Children: according to clinical trials performed in children abacavir is rapidly and well absorbed from

an oral solution administered to children. The overall pharmacokinetic parameters in children are

comparable to adults, with greater variability in plasma concentrations. The recommended dose for

children from three months to 12 years is 8 mg/kg twice daily. This will provide slightly higher mean

plasma concentrations in children, ensuring that the majority will achieve therapeutic concentrations

equivalent to 300 mg twice daily in adults.

There are insufficient safety data to recommend the use of Ziagen in infants less than three months

old. The limited data available indicate that a dose of 2 mg/kg in neonates less than 30 days old

provides similar or greater AUCs, compared to the 8 mg/kg dose administered to older children.

Elderly: the pharmacokinetics of abacavir have not been studied in patients over 65 years of age.

5.3 Preclinical safety data

Abacavir was not mutagenic in bacterial tests but showed activity in vitro in the human lymphocyte

chromosome aberration assay, the mouse lymphoma assay, and the in vivo micronucleus test. This is

consistent with the known activity of other nucleoside analogues. These results indicate that abacavir

has a weak potential to cause chromosomal damage both in vitro and in vivo at high test

concentrations.

Carcinogenicity studies with orally administered abacavir in mice and rats showed an increase in the

incidence of malignant and non-malignant tumours. Malignant tumours occurred in the preputial gland

of males and the clitoral gland of females of both species, and in rats in the thyroid gland of males and

the liver, urinary bladder, lymph nodes and the subcutis of females.

The majority of these tumours occurred at the highest abacavir dose of 330 mg/kg/day in mice and

600 mg/kg/day in rats. The exception was the preputial gland tumour which occurred at a dose of

110 mg/kg in mice. The systemic exposure at the no effect level in mice and rats was equivalent to 3

and 7 times the human systemic exposure during therapy. While the carcinogenic potential in humans

is unknown, these data suggest that a carcinogenic risk to humans is outweighed by the potential

clinical benefit.

In pre-clinical toxicology studies, abacavir treatment was shown to increase liver weights in rats and

monkeys. The clinical relevance of this is unknown. There is no evidence from clinical studies that

abacavir is hepatotoxic. Additionally, autoinduction of abacavir metabolism or induction of the

metabolism of other medicinal products hepatically metabolised has not been observed in man.

Mild myocardial degeneration in the heart of mice and rats was observed following administration of

abacavir for two years. The systemic exposures were equivalent to 7 to 24 times the expected systemic

exposure in humans. The clinical relevance of this finding has not been determined.

In reproductive toxicity studies, embryo and foetal toxicity have been observed in rats but not in

rabbits. These findings included decreased foetal body weight, foetal oedema, and an increase in

skeletal variations/malformations, early intra-uterine deaths and still births. No conclusion can be

drawn with regard to the teratogenic potential of abacavir because of this embryo-foetal toxicity.

A fertility study in the rat has shown that abacavir had no effect on male or female fertility.

17

6.

PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Core:

Microcrystalline cellulose

Sodium starch glycollate

Magnesium stearate

Colloidal anhydrous silica

Coating:

Triacetin

Methylhydroxypropylcellulose

Titanium dioxide

Polysorbate 80

Iron oxide yellow

6.2 Incompatibilities

Not applicable

6.3 Shelf life

3 years

6.4 Special precautions for storage

Do not store above 30°C

6.5 Nature and contents of container

Polyvinyl chloride/foil blister packs containing 60 tablets.

6.6 Special precautions for disposal

No special requirements

7.

MARKETING AUTHORISATION HOLDER

ViiV Healthcare UK Limited

980 Great West Road

Brentford

Middlesex

TW8 9GS

United Kingdom

8.

MARKETING AUTHORISATION NUMBER(S)

EU/1/99/112/001

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

18

Date of first authorisation: 8 July 1999

Date of latest renewal: 8 July 2004

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines

Agency (EMEA) http://www.emea.europa.eu

19

1. NAME OF THE MEDICINAL PRODUCT

Ziagen 20 mg/ml oral solution

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml of oral solution contains 20 mg of abacavir (as sulfate).

Excipients:

Sorbitol (E420) 340 mg/ml

Methyl parahydroxybenzoate (E218) 1.5 mg/ml

Propyl parahydroxybenzoate (E216) 0.18 mg/ml

For a full list of excipients see section 6.1.

3.

PHARMACEUTICAL FORM

Oral solution

The oral solution is clear to slightly opalescent yellowish, aqueous solution.

4.

CLINICAL PARTICULARS

4.1 Therapeutic indications

Ziagen is indicated in antiretroviral combination therapy for the treatment of Human

Immunodeficiency Virus (HIV) infection.

The demonstration of the benefit of Ziagen is mainly based on results of studies performed in

treatment-naïve adult patients on combination therapy with a twice daily regimen (see section 5.1).

Before initiating treatment with abacavir, screening for carriage of the HLA-B*5701 allele should be

performed in any HIV-infected patient, irrespective of racial origin. Screening is also recommended

prior to re-initiation of abacavir in patients of unknown HLA-B*5701 status who have previously

tolerated abacavir (see “Management after an interruption of Ziagen therapy”). Abacavir should not

be used in patients known to carry the HLA-B*5701 allele, unless no other therapeutic option is

available in these patients, based on the treatment history and resistance testing (see section 4.4 and

4.8).

4.2 Posology and method of administration

Ziagen should be prescribed by physicians experienced in the management of HIV infection.

Adults and adolescents: the recommended dose of Ziagen is 600 mg daily (30 ml). This may be

administered as either 300 mg (15 ml) twice daily or 600 mg (30 ml) once daily (see sections 4.4 and

5.1).

Patients changing to the once daily regimen should take 300 mg (15 ml) twice a day and switch to

600 mg (30 ml) once a day the following morning. Where an evening once daily regimen is preferred,

300 mg (15 ml) of Ziagen should be taken on the first morning only, followed by 600 mg (30 ml) in

the evening. When changing back to a twice daily regimen, patients should complete the day's

treatment and start 300 mg (15 ml) twice a day the following morning.

20

Children from three months to 12 years: the recommended dose is 8 mg/kg twice daily up to a

maximum of 600 mg (30 ml) daily.

Children less than three months: the experience in children aged less than three months is limited (see

section 5.2).

Ziagen can be taken with or without food.

Ziagen is also available as a tablet formulation.